Modeling of tissues and organs during development requires deletion of specific cells or groups of cells in a regulated temporal sequence referred to as "programmed cell death". Failure of cell death can result in abnormal development. The long range objectie of the proposed research is to reveal the molecular mechanism of "programmed cell death", which may make it possible to understand and, ultimately, to intervene in many instances of teratogenesis. The hypothesis to be tested is that "programmed cell death" occurs as a result of induction of specific cell surface markers on certain cells which identify them as targets for destruction by cytotoxic macrophages. The specific aims are: 1. to establish whether or not macrophages act as cytotoxic effector cells in regressing tissue, 2. to establish whether or not new cell surface proteins appear prior to cell death and/or the recruitment of macrophages and 3. to establish whether the synthesis of new proteins is an essential requisite of cell death. Perfused anuran tadpole tails (which regress in response to triiodothyronine (T-3) treatment) will be used as the experimental model. The following will be determined to satisfy aim 1: (a) the time after T3 treatment at which cell death begins to occur (as indicated by radiolabeled chromium release) (b) the time course of changes in the rate of degradation of tail muscle contractile proteins (as indicated by the rate of release of 3-methyl-histidine) (c) the time course of macrophage activation (as indicated by the rate of superoxide production) (d) the time course of changes in the rate of collagen degradation (as indicated by the rate of release hydroxyproline) and (e) the effects of inhibitors of macrophage activity on (a)-(d). To satisfy aim, two-dimensional gen electrophoresis and dual isotope incorporation will be used to determine the time course of appearance of new plasma membrane proteins in response to T-3 treatment. To satisfy aim 3 the effects of actinomycin D, cycloheximide and tunicamycin on each of the above parameters will be determined.